Dietary vitamin D and cancers of the oral cavity and esophagus.

BACKGROUND: Data on the association between vitamin D and upper digestive tract neoplasms are limited. METHODS: In two case-control studies in Italy, we examined the relation between dietary vitamin D intake and squamous cell carcinoma of the esophagus (SCCE; 304 cases) and oral/pharyngeal cancer (804 cases). Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by multiple logistic regression. RESULTS: Adjusted ORs for SCCE and oral/pharyngeal cancer were 0.58 (95% CI 0.39-0.86) and 0.76 (95% CI 0.60-0.94), respectively, for the highest tertile of vitamin D intake. Using a reference group of those in the highest tertile of vitamin D who were never/former smokers, ORs were 8.7 (95% CI 4.1-18.7) for SCCE and 10.4 (95% CI 6.9-15.5) for oral/pharyngeal cancer among heavy smokers in the lowest vitamin D tertile; similarly, compared with those in the highest tertile of vitamin D who drank <3 alcoholic drinks/day, corresponding ORs were 41.9 (95% CI 13.7-128.6) for SCCE and 8.5 (95% CI 5.7-12.5) for oral/pharyngeal cancer, among heavy alcohol drinkers in the lowest vitamin D tertile. CONCLUSION: We observed inverse associations between dietary vitamin D intake and risk of SCCE and, perhaps, oral/pharyngeal cancer, which were most pronounced among heavy current smokers and heavy consumers of alcohol.

Intraepithelial carcinoma of the oesophagus: endoscopic morphology.

The endoscopic detection of 18 "early" hypopharyngo-oesophageal carcinomas, has allowed us to perform a detailed study of the morphological correlation between endoscopy and histology (in 10 cases). We have thus defined 4 different endoscopic types of intraepithelial carcinomas; their morphology, mapping and evolution are greatly variable. In high risk groups (heavy smoking and alcohol consumption, ENt-cancer) the multicentricity of intraepithelial carcinomas (80%) entails a thorough endoscopic screening of the upper digestive tract (mouth, pharynx, oesophagus) and of the lower respiratory tract (larynx, trachea and bronchi).

Le reflux gastro-oesophagien: l'apport de l'endoscopie dans l'indication opératoire et les contrôles postopératoires [Gastroesophageal reflux: importance of endoscopy in surgical indications and postoperative control].

Endoscopy constitutes an important investigation in the presence of a gastro-oesophageal reflux. The primary intention is to exclude the possibility of an organic pathology, for example cancer, which has not been demonstrated by other investigative procedures. Accordingly it must provide a detailed exploration of the whole superior digestive tract, from the mouth to the duodenum. Secondly, endoscopy must establish the consequence of the reflux on the mucosa of the lower oesophagus both by a macroscopic and a detailed microscopic description. Peptic lesions are classified according to 4 degrees of severity. The difficulty in evaluating the very early lesions (1st degree) and the advanced stages (4th degree) necessitates systematic biopsies of the lesions. The erythroplasic type of carcinoma in situ can present the same endoscopic changes as a 1st degree peptic lesion, whereas the exclusion of an adenocarcinoma constitutes the major preoccupation at the time of endoscopy of a 4th degree oesophagitis.

Distribution de la morphologie des tumeurs incidentes dans le canton de Vaud [Morphologic distribution of tumors occuring in the canton of Vaud].

After a short presentation of the methodological aspects of cancer registration and morphological coding, the results concerning cancer of the upper digestive tract, lung, testis and ovary were discussed. Some distributions of the main histological types are analysed by age, sex, site and multiple primaries. Known statistical associations are described between morphology and sex for lung cancer and between morphology and controlateral tumor for ovary.

Role of retinoic acid signaling pathway in endoderm antero-posterior patterning

Summary : During vertebrate embryonic development, the endoderm gives rise to the digestive tract and associated organs such as thyroid, lung, liver and pancreas. Earlier studies have shown that extracellular signals coming from the lateral plate mesoderm pattern the endoderm along the antero-posterior axis specifying different organ primordia. An early sign of patterning is the expression of organ-specific genes in restricted endoderm domains. In this study, we focused on the role of the retinoic acid (RA) signaling pathway in the regionalization of the future gut tube along the main body axis. We show that the RA-synthesizing enzyme Raldh2 is expressed in mesoderm close to the endoderm during gastrulation and during somitogenesis. During the same period, all retinoic acid receptors (RARs), which directly activate gene transcription, are expressed in endoderm suggesting that endoderm can be responsive to RA. Activation or inhibition of RA signaling was achieved by adding RA or RAR inhibitors tither on beads or in the medium to cultured chick embryos. Branchial arch (BA) endoderm markers were shifted posteriorly upon depletion of RA at gastrulation, but were not shifted after this stage. Conversely, exposure to exogenous RA repressed the most-anterior BA markers and shifted more posterior BA markers anteriorly. This suggests that graded levels of RA activity in the foregut define gene boundaries and expression levels. The posterior foregut and midget markers Pdxl and CdxA require RA for their expression, but elevated RA does not shift their expression domain along the antero-posterior axis. In addition, we investigated if RA signaling pathway interacts with other signaling pathways to pattern the endoderm. Although both RA and FGFs block anterior foregut marker expression, our experiments suggest that FGF signaling does not depend on RA in anterior endoderm. To validate our chick data in mammalians and evaluate whether RA acts directly on endoderm, we have further generated a conditional loss-of-function system in the mouse, which is still under examination.

Fermentative 2-carbon metabolism produces carcinogenic levels of acetaldehyde in Candida albicans.

Acetaldehyde is a carcinogenic product of alcohol fermentation and metabolism in microbes associated with cancers of the upper digestive tract. In yeast acetaldehyde is a by-product of the pyruvate bypass that converts pyruvate into acetyl-Coenzyme A (CoA) during fermentation. The aims of our study were: (i) to determine the levels of acetaldehyde produced by Candida albicans in the presence of glucose in low oxygen tension in vitro; (ii) to analyse the expression levels of genes involved in the pyruvate-bypass and acetaldehyde production; and (iii) to analyse whether any correlations exist between acetaldehyde levels, alcohol dehydrogenase enzyme activity or expression of the genes involved in the pyruvate-bypass. Candida albicans strains were isolated from patients with oral squamous cell carcinoma (n = 5), autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) patients with chronic oral candidosis (n = 5), and control patients (n = 5). The acetaldehyde and ethanol production by these isolates grown under low oxygen tension in the presence of glucose was determined, and the expression of alcohol dehydrogenase (ADH1 and ADH2), pyruvate decarboxylase (PDC11), aldehyde dehydrogenase (ALD6) and acetyl-CoA synthetase (ACS1 and ACS2) and Adh enzyme activity were analysed. The C. albicans isolates produced high levels of acetaldehyde from glucose under low oxygen tension. The acetaldehyde levels did not correlate with the expression of ADH1, ADH2 or PDC11 but correlated with the expression of down-stream genes ALD6 and ACS1. Significant differences in the gene expressions were measured between strains isolated from different patient groups. Under low oxygen tension ALD6 and ACS1, instead of ADH1 or ADH2, appear the most reliable indicators of candidal acetaldehyde production from glucose.

Peptides from Lactobacillus hydrolysates of bovine milk caseins inhibit prolyl-peptidases of human colon cells.

Prolyl-rich peptides derived from hydrolysates of bovine caseins have been previously shown to inhibit angiotensin converting enzyme (ACE) activity, suggesting that they may also be able to inhibit the enzymatic activities of prolyl-specific peptidases. This study shows that peptides derived from α(S1)-casein and β-casein inhibited the enzymatic activities of purified recombinant matrix metalloprotease (MMP)-2, MMP-7, and MMP-9. The inhibitory efficacy was sequence-dependent. These peptides also selectively inhibited the enzymatic activities of prolyl-amino-peptidases, prolyl-amino-dipeptidases, and prolyl-endopeptidases in extracts of HT-29 and SW480 human colon carcinoma cells, but not in intact cells. They were not cytotoxic or growth inhibitory for these cells. Thus, the prolyl-rich selected peptides were good and selective inhibitors of MMPs and post-proline-cleaving proteases, demonstrating their potential to control inadequate proteolytic activity in the human digestive tract, without inducing cytotoxic effects.

PPARbeta/delta regulates paneth cell differentiation via controlling the hedgehog signaling pathway.

BACKGROUND & AIMS: All 4 differentiated epithelial cell types found in the intestinal epithelium derive from the intestinal epithelial stem cells present in the crypt unit, in a process whose molecular clues are intensely scrutinized. Peroxisome proliferator-activated receptor beta (PPARbeta) is a nuclear hormone receptor activated by fatty acids and is highly expressed in the digestive tract. However, its function in intestinal epithelium homeostasis is understood poorly. METHODS: To assess the role of PPARbeta in the small intestinal epithelium, we combined various cellular and molecular approaches in wild-type and PPARbeta-mutant mice. RESULTS: We show that the expression of PPARbeta is particularly remarkable at the bottom of the crypt of the small intestine where Paneth cells reside. These cells, which have an important role in the innate immunity, are strikingly affected in PPARbeta-null mice. We then show that Indian hedgehog (Ihh) is a signal sent by mature Paneth cells to their precursors, negatively regulating their differentiation. Importantly, PPARbeta acts on Paneth cell homeostasis by down-regulating the expression of Ihh, an effect that can be mimicked by cyclopamine, a known inhibitor of the hedgehog signaling pathway. CONCLUSIONS: We unraveled the Ihh-dependent regulatory loop that controls mature Paneth cell homeostasis and its modulation by PPARbeta. PPARbeta currently is being assessed as a drug target for metabolic diseases; these results reveal some important clues with respect to the signals controlling epithelial cell fate in the small intestine.

Second primary squamous cell carcinoma arising in cutaneous flap reconstructions of two head and neck cancer patients.

Early complications of myocutaneous flap transfers following surgical eradication of head and neck tumors have been extensively described. However, knowledge concerning long-term complications of these techniques remains limited. We report the cases of two patients with a prior history of squamous cell carcinoma of the head and neck (HNSCC), who developed a second primary SCC on the cutaneous surface of their flaps, years after reconstruction. Interestingly, it seems that the well-known risk of a second primary SCC in patients with previous head and neck carcinoma also applies to foreign tissues implanted within the area at risk. Given the important expansion of these interventions, this type of complication may become more frequent in the future. Therefore, long-term follow-up of patients previously treated for HNSCC not only requires careful evaluation of the normal mucosa of the upper aero-digestive tract, but also of the cutaneous surface of the flap used for reconstruction.

Trends in cancer mortality in Switzerland, 1951-1984.

Trends in overall age-standardized, truncated (35-64 years) and age-specific (40 to 49) cancer death certification rates in Switzerland from 1951 to 1984 were analysed. There was a substantial rise in lung cancer mortality in males, with an over 100% increase in overall rates. Thus, in the early 1980's, lung cancer alone accounted for 26% of all cancer deaths in Swiss males. However, male lung cancer rates tended to level off in subsequent cohorts starting from younger middle age in the late 1960's. In females, lung cancer mortality was approximately ten times lower than in males, but rates had been consistently rising since the late 1960's in all age groups. Declines were observed for several neoplasms of the digestive tract: besides stomach (overall decline 68% in males, 77% in females), trends were markedly downwards also for oesophageal cancer in males (-57%), and there was some moderate fall for intestinal sites in both sexes and gallbladder in females. Several trends for other common neoplasms were similar to those observed in other developed countries, such as the declines for (cervix) uteri, the general stability for breast cancer, or the increases in pancreatic cancer and (melanoma) of the skin. A peculiar feature of Swiss data, besides the marked decline in oesophageal cancer in males, was the consistent downward trend in thyroid cancer for both sexes. Thus, overall age-standardized total cancer mortality over the last three decades was moderately upwards in Swiss males, but consistently downwards in females. Male trends were more reassuring in middle age, chiefly in consequence of the flattening in lung cancer rises. Possible interpretations of these trends in terms of aetiological hypotheses (i.e., changes in alcohol drinking and improvements in diet for oesophageal cancer, or reduced prevalence of iodine deficiency for thyroid neoplasms) are discussed.

Differential stress reaction of human colon cells to oleic-acid-stabilized and unstabilized ultrasmall iron oxide nanoparticles.

Therapeutic engineered nanoparticles (NPs), including ultrasmall superparamagnetic iron oxide (USPIO) NPs, may accumulate in the lower digestive tract following ingestion or injection. In order to evaluate the reaction of human colon cells to USPIO NPs, the effects of non-stabilized USPIO NPs (NS-USPIO NPs), oleic-acid-stabilized USPIO NPs (OA-USPIO NPs), and free oleic acid (OA) were compared in human HT29 and CaCo2 colon epithelial cancer cells. First the biophysical characteristics of NS-USPIO NPs and OA-USPIO NPs in water, in cell culture medium supplemented with fetal calf serum, and in cell culture medium preconditioned by HT29 and CaCo₂ cells were determined. Then, stress responses of the cells were evaluated following exposure to NS-USPIO NPs, OA-USPIO NPs, and free OA. No modification of the cytoskeletal actin network was observed. Cell response to stress, including markers of apoptosis and DNA repair, oxidative stress and degradative/autophagic stress, induction of heat shock protein, or lipid metabolism was determined in cells exposed to the two NPs. Induction of an autophagic response was observed in the two cell lines for both NPs but not free OA, while the other stress responses were cell- and NP-specific. The formation of lipid vacuoles/droplets was demonstrated in HT29 and CaCo₂ cells exposed to OA-USPIO NPs but not to NS-USPIO NPs, and to a much lower level in cells exposed to equimolar concentrations of free OA. Therefore, the induction of lipid vacuoles in colon cells exposed to OA utilized as a stabilizer for USPIO NPs is higly amplified compared to free OA, and is not observed in the absence of this lipid in NS-USPIO NPs.

Rat PPARs: quantitative analysis in adult rat tissues and regulation in fasting and refeeding.

PPARs are members of the nuclear hormone receptor superfamily and are primarily involved in lipid metabolism. The expression patterns of all 3 PPAR isotypes in 22 adult rat organs were analyzed by a quantitative ribonuclease protection assay. The data obtained allowed comparison of the expression of each isotype to the others and provided new insight into the less studied PPAR beta (NR1C2) expression and function. This isotype shows a ubiquitous expression pattern and is the most abundant of the three PPARs in all analyzed tissues except adipose tissue. Its expression is especially high in the digestive tract, in addition to kidney, heart, diaphragm, and esophagus. After an overnight fast, PPAR beta mRNA levels are dramatically down-regulated in liver and kidney by up to 80% and are rapidly restored to control levels upon refeeding. This tight nutritional regulation is independent of the circulating glucocorticoid levels and the presence of PPAR alpha, whose activity is markedly up-regulated in the liver and small intestine during fasting. Finally, PPAR gamma 2 mRNA levels are decreased by 50% during fasting in both white and brown adipose tissue. In conclusion, fasting can strongly influence PPAR expression, but in only a few selected tissues.

Preoperative upper gastrointestinal testing can help predicting long-term outcome after gastric banding for morbid obesity.

BACKGROUND: Gastric banding (GB) is one of the most popular bariatric procedures for morbid obesity. Apart from causing weight loss by alimentary restriction, it can interfere with functions of the esophagus and upper stomach. The aim of this study was to evaluate if the results of extensive preoperative upper GI testing were correlated with long-term outcome and complications after GB. METHODS: Using a prospectively maintained computerized database including all the patients undergoing bariatric operations in both our hospitals, we performed a retrospective analysis of the patients who underwent complete upper gastrointestinal (GI) testing (endoscopy, pH monitoring, and manometry) before GB. RESULTS: One hundred thirty-four patients underwent complete testing before GB. Abnormal pH monitoring (increased total reflux time, increased diurnal reflux time, increased number of reflux episodes) predicted the development of complications and especially pouch dilatation and food intolerance. The mean De Meester score was higher among patients who developed complications than in the remaining ones (25.4 vs 17.7, P=0.03). High lower esophageal sphincter pressure also predicted progressive long-term food intolerance. Endoscopic findings were not predictive of the long-term outcome. CONCLUSIONS: There is some association between the function of the upper digestive tract and long-term complications after gastric banding. Abnormal pH monitoring predicts overall long-term complications, especially food intolerance with or without reflux, and pouch dilatation, and a high lower esophageal sphincter pressure predicts long-term food intolerance. Extended upper gastrointestinal testing with endoscopy, 24-h pH monitoring, and esophageal manometry is probably worthwhile in selecting patients for gastric banding.

Prévalence des maladies infectieuses au Centre hospitalier universitaire vaudois [Prevalence of infectious diseases at the Vaud University Hospital Center].

The prevalence of infectious diseases at our hospital (Centre hospitalier universitaire vaudois, Lausanne [CHUV], 900 beds) was studied retrospectively over a two years period (1980-1981). The medical diagnosis of 30203 patients recorded in the computerized medical archives, representing 93% of the patients admitted during the period of observation, was reviewed. To assess the reliability of the computerized data, quality control was carried out through detailed analysis of all the histologically proven appendicitis recorded during 1981. 88% of the histologically proven appendicitis were registered in the computer and the diagnosis was specific in 87% of cases. An infectious disease was the primary reason for admission in 12.8% of the patients (3873) during the study period. Altogether, 20.2% of patients presented with an infection during their hospital stay. Because of the retrospective nature of the study it was not possible to determine whether these additional infections were nosocomially acquired. The organ systems most frequently infected were the respiratory tract (28.5% of all infections), the digestive tract (20.5%), the skin and osteoarticular system (16%) and the urogenital tract (11.6%). An infection was the primary reason for admission of 40.2% of the patients hospitalized in the dermatology service, of 19.7% of patients admitted in internal medicine, of 15-17% of the patients admitted in pediatrics, ENT and general surgery, and of 1-2% of the patients admitted in neurosurgery and radiotherapy. These observations highlight the continuing importance of infectious diseases in a modern hospital, in spite of high socio-economic levels, stringent hygiene and epidemiologic measures, and modern antibiotic availability.

In vitro selection of bacteria with potential for use as probiotics in marine shrimp culture

The objective of this work was to isolate strains of lactic acid bacteria with probiotic potential from the digestive tract of marine shrimp (Litopenaeus vannamei), and to carry out in vitro selection based on multiple characters. The ideotype (ideal proposed strain) was defined by the highest averages for the traits maximum growth velocity, final count of viable cells, and inhibition halo against nine freshwater and marine pathogens, and by the lowest averages for the traits duplication time and resistance of strains to NaCl (1.5 and 3%), pH (6, 8, and 9), and biliary salts (5%). Mahalanobis distance (D²) was estimated among the evaluated strains, and the best ones were those with the shortest distances to the ideotype. Ten bacterial strains were isolated and biochemically identified as Lactobacillus plantarum (3), L. brevis (3), Weissella confusa (2), Lactococcus lactis (1), and L. delbrueckii (1). Lactobacillus plantarum strains showed a wide spectrum of action and the largest inhibition halos against pathogens, both Gram-positive and negative, high growth rate, and tolerance to all evaluated parameters. In relation to ideotype, L. plantarum showed the lowest Mahalanobis (D²) distance, followed by the strains of W. confusa, L. brevis, L. lactis, and L. delbrueckii. Among the analyzed bacterial strains, those of Lactobacillus plantarum have the greatest potential for use as a probiotic for marine shrimp.